SU1189348A3 - Method of producing esters of alkoxyvincaminic acid and/or esters of alkoxyapovincaminic acid or their epimers,racemates,optically active isomers or their acid physiologically acceptable salts - Google Patents

Abstract

The invention relates to a new process for the preparation of alkoxyvincaminic acid esters of the formula (I) <IMAGE> (I) and/or alkoxyapovincaminic acid esters of the formula (II) <IMAGE> (II) wherein R1, R2 and R3 independently stand for alkyl groups having from one to 6 carbon atoms. The compounds of the formulae (I) and (II) are pharmaceutically active, thus some of them show psychostimulant activity.

Description

where R has the indicated value, is reacted with an acrylic ester of the general formula CHg CH - COORf where R is C, - C alkyl, in a halogenated hydrocarbon medium, and then treated with an inorganic acid HB to form an alkoxyhexahydroindoloquinolysinium ester of general formula V

where R and R have the indicated meanings;

B is an acid residue, which is then pinned off by an N-double bond with sodium borogvridrida in a lower aliphatic alcohol medium and the alkoxyoctohydroindoloquinolizine ester obtained of the general formula YI.

, B OOC-CH -CH k.

where R and R have the indicated meanings, in the form of a salt, are treated with a strong organic base in an aromatic hydrocarbon medium and the resulting alkoxygomemburnan of the general formula VII

omg

where R has the indicated values, the aromatic hydrocarbon medium is oximeted and the alkoxy-derived turbulence of the general formula VIII obtained is the IR spectrum (KBr): 3250, 1620, 1565, 1540, 1260. Example 2. 1-Ethyl-1- (2-methoxycarbonyl-ethyl) -10-methoxy-1, 2,3,4,6,7-hexahydro-12H-indolo (2,3-a) quinolizinium-perchlorate. 121 mg (0.3 mmol) of 1-ethyl-10-method 1 si-1, 2,3,4,6,7-hexahydro-12H-indol (2,3-a) quinolizinium-perchlore (example 1) is stirred at room temperature for 10 minutes in a mixture of 7.5 ml of water, 0.5 ml of 10% aqueous sodium hydroxide solution and 3 ml of dichloromethane. The organic phase is then separated, dried with anhydrous solid potassium carbonate, filtered. The filtrate is stirred with Gf2 ml of methyl acrylic ester and then allowed to stand for 20 hours. Transfer the valuable reagent and solvent to the solvent and evaporate in vacuo. 125 mg of the oil obtained after evaporation is dissolved in 1 ml of methanol and reacted with 70% aqueous perchloric acid to obtain perchlorate. Obtain 52 mg (37%) of the product, so pl. 125-127 C. IR spectrum. (KVG): 3280, 1720, 1580, 1520, 1355, 1080. Example 3. (+) - 1k-Ethyl-1- (2-methoxycarbonyl-ethyl) -10-methoxy-1, 2,3,4,6,7,12,12 lb-octahydroindolo (2,3-a) quinolizin and (±) -1 y-ethyl-1 / 3- (2-methoxycarbonyl-ethyl) -10-methoxy-1,2,3,4,6,7,12, 12ÜX oxhydroindolo (2,3-a) quinolizin. 52 mg (Ojll mmol) 1-ethyl-1- (2-methoxycarbonyl-ethyl) -10-methoxy-1, 2,3,4,6,7-hexahydro-12H-indoLo (2,3-a) quinolizinium- perchlorate (Example 2) is dissolved in 10 ml of methanol. At this time, 8 mg of borohydride sodium is added to the solution. The mixture was stirred for 30 minutes and after adding one drop of acetic acid, methanol was distilled off. The residue is partitioned between 3.5 ml of dichlorome and 1 ml of a 10% aqueous solution of sodium carbonate. Organic phase. dried with anhydrous. magnesium sulfate and then evaporated. The residue after evaporation consists of 50.3 mg of a mixture, which is divided into components a and b by preparative chromatography (R. (and more than RJ b, benzene and methanol in a ratio of 8: 2). B as substance a, 9.6 mg (23%) (±) -1o (-ethyl-1 / 3- (2-methoxycarbonyl-ethyl) -10-methoxy-. -1,2,3,4,6,7 , 12,12m-octagidroindolo (2,3-a) quinolysin, mp 120-123 0. IR spectrum (KBr): 1710, 1.630, 1460, 1 440, 1 256, 1150, 1030. MS, m / e (%): 370 (m, 59), 369 (61), 297 (100), 227 (23), 215 (10), 199 (20), 107 (16). As a substance b, 13 mg is obtained (29%) (+) - 10-ethyl-1 / 5- (2-methoxycarbonyl-e-tyl) -10-methoxy-1,2,3,4, 6,7,12,12bot -crypt idroindolo (2,3-a) quinolizine hydrochloride, mp 195196® C. Example 4. (-) - 1a, -ethyl-1 / 3- (2-methoxycarbon-ethyl) -8-methoxy, 3,4,6,7,12,12Ь /} - octahydroindolo (2,3-a) quinolysin. 0.30 g (13.0 mmol) of metallic sodium is dissolved in the absence of moisture in a stream of nitrogen in 3.7 ml of absolute methanol, then, with constant stirring, successively 6.25 ml of absolute dimethylformamdda, 0.625 g (3.28 mmol) of freshly prepared copper iodide (T) and 0.50 g (1.3 mmol) (+) - 3 (S), 17 (S) -9-6poM-14-oKco-E -moyoburnan The reaction mixture is under nitrogen for 20 minutes in a bath at 1 10 ° C. After cooling, the reaction mixture is made up to 25 ml with ice water, shaken with 15 ml of ethyl acetate, the separated inorganic substances are filtered off and washed on the filter with 10 ml of ethyl acetate. The filtrate is again extracted with 4x8 ml of ethyl acetate. The combined organic phases are washed with 10 ml of water, dried with magnesium sulfate and evaporated in vacuo. 0.54 mg of an oily product is obtained. This product is dissolved in 2.5 ml of acetonitrile, the solution is brought to pH 5 with hydrochloric acid methanol, and the material is filtered and washed with 1 ml of acetonitrile. Obtain 0.25 g (48.7%) of the product, so pl. 241-242 C (acetonitrile). From the hydrochloride portion, release the base as follows. The hydrochloride is dissolved in dichloromethane and the solution is shaken with 5% sodium bicarbonate solution. The organic phase is separated, dried and freed from solvent. The oily substance obtained is crystallized from methanol. The base melts at 160-162 C. o

W –111, oi, –133.6 (, 01, dichloromethane).

IR spectrum (HBG): 3500 (indole-HH), 1725 (complex ether-CO), 1608, 1580 (arom.) See

MS, m / e (%): 370 (M, C2g ,, 72), 369 (76), 355 (9), 339 (9), 327 (0.8), 311 (1.5), 207 ( 100), 283 (3) 281 (3), 267 (3), 251 (1.5), 241 (3),

227 (22), 215 (11), 200 (29), 185 (9).

Example 5. 3 (S), 17 (S) -11-Methoxy-14-oxo-E-homoburnan, 0.76, g (1.87 mmol) (-) - 1 K-ethyl-1 / 5- ( 2-methoxycarbonyl-ethyl) -10-methox -1,2,3,4,6,7,7,12,12 Lo (; - octahydroindolo (2,3-a) -quinolizin-hydrochloride (example A) is stirred in 15 ml of absolute toluene under nitrogen at room temperature with 0.72 g (7.42 mmol) of sodium-sec-butylate for 5 hours. Then the reaction mixture was diluted with a solution of 0.8 g in 10 ml of water and stirred for 5 minutes. the phase is separated and the aqueous phase is re-extracted with 4x5 ml of dichloromethane. The combined organic phases are dried with a solid anhydrous magnesium sulfate, filtered, and the filtrate is freed from the solvent in vacuo.

The oily residue (0.60 g) is crystallized from 2 ml of methanol. The crystals that separated were filtered out, washed with 5 ml of methanol and then dried; 267 mg of product are obtained.

From the mother liquor, preparative chromium chromatography (silica gel Rp254 + Ebb benzene: methanol 14: 3, Rf of the starting material less than Rf of the final product, developing by elution with acetone) can be recovered by an additional 65 mg of product.

Total yield: 332 mg (52.5%), mp, 138-140 ° C (from methanol).

IR spectrum (CDG): 1685 (amide-CO), 1600 (arom.) Cm

M +, m / e (%): 338 (M, .NO-, 100), 337 (82), 323 (2), 310 (11), 309 (16), 296 (8), 295 (5) , 282 (18), 281 (20), 267 (9), 168 (10).

Example 6. C +) - 3 (S), 17 (S) -11-Methoxy-14-oxo-15-hydroximino-E-homoeburnan.

To a solution consisting of 0.34 g (1.00 mmol) 3 (8), 17 (8) -11-methoxy-14-oxo-E-homoeburnane (Example 5) in 4.6 ml of toluene, is added in a nitrogen atmosphere, 0.92 ml of sec-butyl nitrite IO, 29 g of potassium tert-butylate. The reaction mixture is stirred at room temperature for 20 minutes.

Then, 0.77 g of ammonium chloride in 5 ml of water is added to the mixture. After temperature stirring, the organic phase is separated and the aqueous phase is extracted with 3x5 ml of dichloromethane. The combined organic phases are dried with magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo. The oily residue (0.34 g) is dissolved in 3 ml of acetonitrile, the pH of the solution is adjusted to 4 with hydrochloric acid methanol and the precipitated hydrochloride is filtered off. The product is washed with 1 ml of acetonitrile and dried.

Get 185 ml (46%) of the product so pl. 228-230s (from acetonitrile decomposition).

IR spectrum (KB)): 3400 (OH), 1700 (amide-CO), 1630 (), 1610 (arom.

M, m / e (%): 367 (M ,, 0 ,, 100), 366 (62), 351 (19), 350 (28), 338 (26), 337 (78), 323 (19i 320 ( 62), 310 (10), 295 (10), 295 (10), 293 (14), 281 (18), 267 (16), 200 (9.4), 199 (13)

W —Y25, Hf -, 9 (c 0.82, dichloromethane).

Example 7. (-) - loi-ETSh1-1L- (2-methoxycarbonyl-2-hydroximinoethyl) -10-methoxy-1,2,3,4,6,7., 12,12 hD-octahydroindolo (2,3- a) quinolysin.

0.40 g (1.08 mmol) (f) -3CS), 7 (S) -11-methoxy-14-oxo-15-hydroximino-E-homoburnane: (Example 6) is boiled in 5 ml of absolute methanol in the presence of 0.13 g of sodium methylate in the absence of moisture for 1 h.

After cooling, sodium methylate is decomposed with acetic acid and the solution is evaporated in vacuo to a dry state. The residue is diluted with 2 ml of water and the pH of the solution is adjusted to 8 with a diluted 1: 1 ratio of aqueous ammonia. The solution is extracted with 3x5 ml of dichloromethane. The organic phase is dried with anhydrous magnesium sulphate, filtered and the filtrate is evaporated. The oily residue (0.35 g) is dissolved in 1 ml of methanol. The pH of the solution is adjusted to 4 hydrochloric acids with methanol. The hydrochloride which is separated out is filtered off, washed first with 0.5 ml of methanol and then with 1 ml of ether and dried. Get 225 mg (47.8%) of the product, so pl. 221-222 C (methanol). IR spectrum (KB): 3300 (NH, OH); 1720 (ester-CO), 1618 (arom.) CmH MS, m / e (%): 399 (M ,, 100), 398 (57), 384 (15), 383 (30), 382 (56 ), 372 (6.9), 370 (16), 368 (9.2) 340 (25) ,. 328 (13), 322 (24), 308 (8.9), 297 (36), 267 (13). Optical activity of the base: AM1, ° -95.2 °; M | J, -121.1 °. (from 0.64, chloroform). Example 8. (-) - 1 ° C-Ethyl-1 / - (2-methoxycarbonyl-2-hydroximino ethyl) -10-methoxy-1,2,3,4,6,7,7,12,1 2Hc6-octagidroindolo- (2 , 3-a) quinolysin. 61 g (26.5 mmol) of metallic sodium are dissolved in the absence of moisture in a stream of nitrogen in 765 ml of absolute methanol. To the solution is added successively 6.75 mg of absolute dimethylformamide, 1.275 g (0.63 mmol of freshly prepared copper iodide (1) and a solution 0.93 g (2.24 mmol) of (+) - 3 (S), 17 (S) -11-bromo-4-okso-15-hydroxyimino-E-goma-borane in 6 ml of absolute dimethylformamide. The reaction mixture is stirred in an atmosphere nitrogen at 110 ° C for 3 hours. After cooling, ice water is added to the mixture to 25 ml. The pH of the solution is adjusted to 8 with acetic acid. The solution is shaken from 25 The organic phase is separated and the aqueous phase is extracted with 3x10 ml of ethyl acetate. The combined organic phases are washed with 2x15 ml of water, dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. the residue (0.59 g) was dissolved in 2 ml of methanol, the solution was adjusted to pH 4 (methanol, HCl), the resulting substance was filtered, washed with 0.5 ml of methanol and then dried. Obtain 0.38 g (38.7%) of hydrochloride, so pl. 221-222C (methanol). IR spectrum (KVG): 3300 (W, OH), 1720 (ester-CO), 1618 (arom.) Cm, m / ti (%): 399 (M, C2HNG9M, 04, 100), 398 (57 ), 384 (15), 383 (20), 382 (56), 372 (6.9), 370 (16), 368 (9.2); 340 (9.2), 340 (25), 323 (1), 322 (24), 308 (8.9), 290 (36), 267 (13). Ulb -95,;. ;;, -121.1 ° (c 0.64, chloroform). Example 9. 1-Ethyl-1 / 3- (2-methoxycarbonyl-2-hydroximino-ethyl) -1 p-bromo-1,2,3,4,6,7,7,12,12 (; - octahydroindolo (2,3 -a) quin-lysine 0.20 g (0.48 mmol) (+) - 3 (S), 17 (S) -11-bromo-14-oxo-15-hydroxy-minimo-E-homoburnane is boiled in 2 ml absolute methanol in the presence of 60 ml of sodium methylate in the absence of moisture for 1 hour Sodium methylate is decomposed with acetic acid () and the solvent is distilled off in vacuo. The oil obtained after evaporation as a residue is dissolved in 5 ml of dichloromethane and the solution is extracted with 1 ml. % aqueous solution of sodium carbenate. The organic phase from gels, dried with anhydrous magnesium sulfate, filtered, and the filtrate evaporated in vacuo.The resulting oily residue (0.16 g) was crystallized with 1 ml of methanol to give 0.12 g (56%) of product, mp 191-193 ° C (methanol). IR spectrum (KB): 3400 (NH, OH), 1698 ester-CO) see Example 10. 1c-Ethyl-1 / (2-methoxycarbonyl-2-hydroximino-ethyl) -10-methoxy-1,2,3,4,6,7,12, 1 2La (, - octahydroindolo (2,3- a) quinolysin 84 mg (3.65 mmol) of metallic sodium are dissolved in the absence of moisture in a stream of nitrogen in 1 ml of absolute methanol, 1.8 ml of absolute dimethylformamide, 0.176 g (0.91 mmol) of copper iodide are added successively to the solution (1) and 0.14 g (0.31 mmol) 1 ° (, ethyl 1D- (2-methoxycarbonyl-2 hydroximino-ethyl) -10-bromo-1,2,3,4, 6,7,12 , 1 2HO6-octahydroindolo (2,3-a) quinolysin (Example 9). The reaction mixture was stirred under nitrogen at 110 ° C for 3.5 hours. Then see The mixture is made up to 10 ml with water and acetic acid, the solution is adjusted to pH 8 and the mixture is diluted with 5 ml of ethyl acetate. The inorganic substance precipitated is removed by filtration. The organic phase is separated from the filtrate, the aqueous phase is extracted again with 3x2 ml of ethyl acetate and the combined organic the phases are washed with 1 ml of water, dried with anhydrous magnesium sulfate, filtered, and evaporated. vacuum. The resulting oil (70 mg) is dissolved in 0.5 MP of methanol, the pH of the solution is adjusted to 4 with hydrochloric methanol, the precipitated hydrochloride is filtered off, washed with 0.2 ml of methanol, then 1 ml of ether, and dried. 40 mg (33%) of the product are obtained, the physical and chemical properties of which correspond to the properties of the product obtained according to examples 7 and 8. Example 11. (+) - 3 (S), 17 (5) -Vinc, and (+) - 3 (S), 17 (8) -apovincin. A solution prepared with 1 ml of acetic acid and 16 ml of 5% aqueous sulfuric acid is 0.24 g (0.55 mmol) of (-) - 1 "(. Ethyl 1 ft- (2-methoxycarbonyl-2-hydroxy-hydroxymethyl) ethyl) -10-methoxy-1, 2,3,4,6,7,12,12Lo6-octahydroindole (2,3-a) quinolizine hydrochloride (examples 7, 8 or 10) is held for 3 hours at 110 ° C. Under ice cooling, the pH of the solution was adjusted to 8 with concentrated aqueous ammonia and the basic solution was extracted with 3x5 ml of dichloro methane. The combined organic phases were dried with solid anhydrous magnesium sulphate and then filtered and freed from solvent The oil obtained as a residue (0.23 g) is crystallized from 1 ml of methanol for 24 hours. The crystals are filtered, washed with 0.4 ml of cold methanol and then dried. 68 mg (32%) is obtained (+ -vincin which, according to its chemical and physical properties, corresponds to the standard isolated from the plants. Mp 212c The standard, also melting at 212 C, shows no lower melting point when mixed with the product. IR spectrum (HBG): 3400 (OH), 1730 (complex Efir-CO), 1618 (arom.) Cm -38 °; M |,% .42 ° (s 1.03, pyridine). Methyl mother liquor is purified by preparative chromatography (silica gel benzene: methanol 14: 3, solvent - acetone). From the zone with twice the Rf value, 45 mg (21%) of (+) - apovincine is given in the form of an oily substance and is identified in the form of D-tartrate. The tartrate is crystallized from 0.5 ml of a mixture consisting of acetone and ethyl acetate. The product is identical in its physical and chemical properties with vegetable apovincinthartrate. M.p. 111 C (acetone-ethyl acetate). IR (KBg): 3400 (OH), 1718 (ester-CO), 1630 (), 1605 (arom.) See M ,, ° 170.1% WJ °, -.62.6 (with 0.6 pyridine). An additional 5 ml of (+) - vincine was taken from the next zone. From the zone with the lowest Rf value, 10 mg of unreacted starting material is returned. Example 12. (+) - 3 (S), 17 (S) -Apovintsin. 44 mg (0.10 mmol) (-) - 1o-ethyl-1 - (2-methoxycarbonyl-1-2-gndroximino-ethyl) -10-methox-1,2,3,4, 6,7,12,1 2Bo-octahydroindolo (2,3-a) quinolizin-gnidrochloride (example 7 or 9) is dissolved in a previously prepared mixture of 3.75 ml of methanol and 1.35 ml of concentrated sulfuric acid. The solution is heated for 1 hour in a water bath. After cooling, the mixture is made up to 10 ml with ice water, with external cooling, the mixture is alkalinized with concentrated aqueous ammonia and then extracted with 3x5 ml of dichloromethane. The combined organic phases are dried with anhydrous magnesium sulphate, filtered, and the solvent is removed from the filtrate in vacuo. The oily residue (43 mg) is purified by preparative chromatography (silica gel, benzene: methanol 14: 3, solvent acetone).

Claims (1)

A method for producing alkoxyvincamic acid esters of general formula J I b where R and R are C (-C4 alkyl or their epimers, racemates, optically active isomers or their physiologically acceptable acid salts, characterized in that, in order to simplify the process, the racemic or optically active alkoxyindole derivative of the general formula III where R ¹ and P ^g have the indicated meanings, are reacted with phosphorus oxychloride, followed by reaction with an inorganic acid and the resulting alkoxyhexahydroindolequinoliniumium salt of general formula IV a and / or alkoxyapovincamic acid esters of general formula II where R * has the indicated meaning; A is the acid residue of an inorganic acid, treated with an inorganic base, the obtained hexahydroindolequinolizine of the general formula IV ^Λ where R ^f has the indicated meaning, is reacted with an acrylic ester of the general formula CH _g = CH - COOR * where R ² - C, - SC apkyl, · In a halogenated hydrocarbon medium, after which they are treated with HB inorganic acid to give an alkoxyhexahydroindolequinolisinium ester of the general formula V / 7 where R and R have the indicated meanings; B is an acid residue, which is then saturated at the N-double bond with sodium borohydride in a lower aliphatic alcohol medium, and the obtained hydroxyindolequinolysine alkoxyocto ester of the general formula YI 'where R ^z has the indicated meanings, is oxidized in an aromatic hydrocarbon medium and the resulting alkoxy-homoeburnanoxime of the general formula VIII where R * has the indicated meaning, is reacted with an alkanol of the general formula R OH, where R has the indicated meaning, in an alkaline medium in the presence of copper iodide and the resulting alkoxy-g ester droksimino-oktagidroindolohinolizina general formula IX R ² 00C-C-CH _z < \\ NOH where R * and R ² have the indicated meanings where R and R have the indicated meanings, are treated with a strong organic base in an aromatic hydrocarbon medium in the form of a salt, and the resulting alkoxy homoeburnan of general formula VII is treated with an aqueous mixture of acetic and sulfuric acids to obtain a mixture of compounds of the general formula I and II, which is further separated, or a compound of formula IX is treated with concentrated strong inorganic acid to obtain a compound of general formula D, followed by isolation of the desired products in free form or in ideally physiologically compatible acid salts, the separation of optically active isomers being carried out at an arbitrary step in the process.